Dibenzyl-bis-ammonium salts



United States Patent DIBENZYL-BIS-AMlVlONIUM SALTS No Drawing.Application June 2, 1952, Serial No. 291,297

1 Claim. (Cl. 260567.6)

This invention relates to new aryl quaternary ammonium salts.

A primary object of the invention is the embodiment of a new group ofcompounds characterized by a potent curare-like activity and by freedomfrom undesired side efiects such as hypotension, respiratory paralysis,bronchiospasm, salivation, etc.

This object is realized, according to the present invention, by a newgroup of aryl quaternary amines which correspond to the formula whereinR stands for a lower alkyl group, such as methyl, ethyl, propyl, butyl,etc., R stands for a lower alkyl group (which may be the same as ordifierent from the lower alkyl group represented by R) or for an aralkylradical, such as benzyl, alkylated benzyl, alkoxylated benzyl,halogenated benzyl, etc., and X stands for a halogen atom as forexample, a chlorine, bromine or iodine atom. These compounds fulfill theaforementioned desiderata in that, in addition to a high curarelikeactivity, they do not cause the aforesaid undesired side effects. Thecompounds are thus useful therapeutically, and may be administeredintramuscularly, intravenously or orally. The activity by oraladministration is of great importance for the treatment of Parkinsonsdisease to reduce muscle tremors.

The compounds of the invention are prepared by refiuxing for example a4,4'-diamino-dibenzyl in solution with anexcess of an alkylating agentsuch as an alkyl halide or a dialkyl sulfate together with an alkalimetal hydroxide such as sodium hydroxide or potassium hydroxide,according-in the case of 4,4'-diarnino-dibenzyl itself to the followingreaction scheme:

CH2- NHz GH2- I (R RX X R (III) MOH /R I V RX X R i MOQX heatl {RX V)wherein R, R and X have the previously indicated significances and Mstands for an alkali metal.

When the alkylating agent is methyl iodide, the product,dibenzyl-4,4-bis-trimethylammonium iodide crystallizes from the reactionmixture. .When the "alkylating agent is an alkyl halide containing twoor more carbon atoms, it is possible to stop the alkylating process atthe tertiary amine stage (II) and then to complete quaterna- \ion in anadditional step wherein if desired another lkylating agent is employed.

The quaternary ammonium compounds (III), when iubjected to heat, losealkyl halide to form the bis-tertiary amino dibenzyl derivative whichthen may be quaternized using the same or a different alkylating agentor an aralkylating agent to produce the quaternary compounds (IV).

The iodide salt may be converted to the bromide or the chloride salt bytreating the quaternary iodide with silver bromide or silver chloriderespectively.

Examples of suitable alkyl and aralkyl halides are methyl iodide, ethyliodide, propyl iodide, benzyl bromide, ethyl bromide, ethyl chloride,p-methoxybenzyl bromide, p-methylbenzyl bromide and the like.

Alternatively, 4,4'-diamino-dibenzyl is alkylated by heating underpressure with an alcohol at a temperature of 200 C. In this waydiamino-dibenzyl may be alkylated with ethyl alcohol, propyl alcohol,and the like.

The following examples set forth representative exemplary embodiments ofthe invention, and these examples are intended to be illustrative andnot limitative. In these examples, parts by weight bear the samerelation as to parts by volume as does the kilogram to the liter.Temperatures are expressed in degrees centigrade. Percentages are byweight. All melting points are uncorrected.

Example I 25 parts by weight of 4,4-diamino-dibenzyl are refluxed in 300parts by volume ethanol with 33 parts by weight of sodium hydroxide andparts by volume of methyl iodide. After six hours of refluxing, duringwhich time the crystalline product slowly separates, the reaction iscomplete. The crystalline material is separated and, byrecrystallization from hot water, yields dibenzyl-4,4'-bis-(trimethylammonium iodide) H3O CH2 HsC NCH2CH2-@-NClis HaC i i.CH: which melts at 235240 (with decomposition).

Example 2 Example 3 10 parts by weight ofdibenzyl-4,4-(trimethylammonium iodide) are heated at 250 under 15 min.pressure for /2 hour. The residue is extracted with benzene, and thebenzene extracted with aqueous hydrochloric acid. On making the latterextract alkaline with ammonia, 4,4'bis-(dimethylamino)-dibenzylseparates. The product, which corresponds to the formula H3O CH3 H30 CH3melts at 152-156", after crystallization from ethanol. By reaction withmethyl iodide in alcohol solution, this amine can be converted intodibenzyl-4,4'-bis-(trimethylammonium iodide).

Ex m l 4 1 5 parts of 4,4-bis-(dimethylamino)-dibenzyl are re uxe.Qvernight with 6 P r b q um .of th l d de in 50 parts by volume ofethanol-benzenemixture (:1).

Ethyl acetate is added to complete the erystallization of the quaternarysalt. It is recrystallized from 95% ethanol, yielding dibenzyl-4,4-bis-.(dimethylethylammonium iodide) H: 1 I C2135 Whieh melts at 2l3-217(with decomposition).

Example 5 By substituting 6 parts by volume of propyl iodide for theethyl iodide employed in Example 4 and otherwise proceeding as describedin the latter, there is obtained dibenzyl 4,4 bis(dimethylpropylammonium iodide) which melts at l93197 (withdecomposition).

Example 6 H3O Bl Br CH; which melts at 150-153 (with decomposition).

Example 7 20 parts by weight of 4,4-diamino-dibenzyl are refiuxed for 12hours with 31 parts by volume of ethyl iodide and 15.2 parts by weightof sodium hydroxide in 300 parts by volume of ethanol. The solution isconcentrated to a small volume, the formed sodium iodide is filteredoff, and water added to the filtrate. An oil precipitates, whichcrystallizes on standing. It is recrystallized from methanol to yield4,4-bis-(diethylamino)-dibenzyl, melting at -83". Reaction with methyliodide in the manner hereinbefore described yieldsdibenzyl-4,4'-bis-(diethylmethylammonium iodide) which melts at 225-230(with decomposition); and reaction with benzyl bromide yieldsdibenzyl-4,4-bis-(benzyldiethylammonium bromide) which melts at 235-241(with decomposition) Example 8 20 parts by weight of4,4-diamino-dibenzyl are refluxed for 12 hours with 20 parts by weightof sodium hydroxide and 60 parts by volume of ethyl iodide in 300 partsby volume .of ethanol. The mixture is concentrated to a small volume,the sodium iodide which crystallizes is removed by filtration, and wateris added to the filtrate. The gummy material which precipitates isshaken with an excess of freshly-prepared silver chloride (about partsby weight) in about 500 parts by volume of water. The silver salts arefiltered off, and the aqueous portion evaporated to dryness in vacuo.The solid residue is extracted with a minimum quantity of hot ethylalcohol, and any sodium chloride which remains undissolved is filteredotf. Ethyl acetate is added to the filtrate until turbidity sets in and,on cooling, crystalline dibenzy1-4,4'-bis-(triethylammonium chloride),melting at 216-221 with decomposition, is obtained.

Example 9 5 parts by weight of 4,4T-bis-(dimethylamino)-dibenzyl and 6.9parts by weight of p-methylbenzyl bromide are refluxed for /2 hour in 20parts by volume of acetone. The oil which separates is recrystallizedfrom ethanolethyl acetate to yielddibenzyl-4,4-bis-(dimethyl-pmethylbenzyl-ammonium bromide); meltingpoint 194- 198 (decomposition).

Example 10 5 parts by weight of 4,4-bis-(dimethylamino)-dibenzyl and 8.1parts by weight of p-nitrobenzyl bromide are dissolved in 20 parts byvolume of dry acetone and allowed to stand overnight at room temperature(e. g. 20 to 30). An oil gradually precipitates which is recrystallizedfrom ethanol-ethyl acetate to yield dibenzyl- 4,4 bis (dimethyl pnitrobenzyl ammonium bromide); melting point -143 (decomposition).

Example 11 5 parts by weight of 4,4-bis-(dimethylamino)-dibenzyl and 6parts by'weight of p-chlorobenzyl chloride are refluxed for 5 minutes in25 parts by volume of ethanol. Ethyl acetate is added until a cloudinessappears. The small amount of gum which precipitates is separated and onfurther standing the desired crystalline quaternary compound, dibenzyl4,4 bis (dimethyl p chlorobenzyl ammonium chloride) is obtained; meltingpoint 123-126.

Proceeding similarly using 5.05 parts by volume of m-methylbenzylbromide instead of the p-chlorobenzyl chloride, there is obtaineddibenzyl-4,4',-bis-(dimethylm-methylbenzyl ammonium bromide); meltingpoint 143-146".

Example 12 2 parts by weight of 4,4-bis-(dimethylamino).-dibenzyl and 3parts by weight of p-methoxybenzyl bromide are refluxed for 5 minutes in25 parts by volume of ethanol. Ethyl acetate is added to precipitate theoily product which is redissolved in ethanol and reprecipitated withethyl acetate to free the preparation from unreacted starting material.The oil is dried in vacuo to yield dibenzyl-4,4-bis-(dimethyl-p-methoxybenzyl-ammonium bromide) in a resinous state.By dissolving in water, a solution is obtained which is suitable fortherapeutic purposes. By dissolving in water and adding an aqueoussolution of picrylsulfonic acid, there is obtained the dipicrylsulfonatesalt; melting point (decomposition).

Having thus disclosed the invention, What is claimed is:

Dibenzyl-4,4-bis-(triethylammonium chloride) References Cited in thefile of this patent UNITED STATES PATENTS Crossley Dec. 30, 1952 OTHERREFERENCES IIegmann et al.: Ber. deut. chem, vol. 20 (1887), p.

